Pharmaceutical composition for the treatment of so-called restless legs

ABSTRACT

A pharmaceutical composition for the treatment of so-called restless legs is disclosed, which composition comprises a combination of: A) quinine, preferably, in the form of a pharmaceutically acceptable acid addition salt thereof; and B) a compound selected from the group consisting of B1) compounds of general formula (I) wherein R 1  is hydrogen or a straight or branched alkyl group, having 1-4 carbon atoms, R 2  and R 3 , which are equal or different, each represents hydrogen, a halogen atom, a straight or branched alkyl or alkoxy group having 1-4 carbon atoms, or a trifluoromethyl group, preferably in the form of a pharmaceutically acceptable salt thereof; and B2) compounds of general formula (II) wherein X is hydrogen or a halogen atom, preferably chlorine, and R 4  is a methyl, ethyl or phenyl group together with conventional pharmaceutically acceptable carrier substances. The invention also relates to the use of quinine and substance of general formula (I) or (II) for the production of a pharmaceutical composition for the treatment of restless legs and a method of treatment for restless legs in which therapeutic doses of a compound of formula (I) or (II) are administered to the patient in combination with quinine.

The present invention relates to a pharmaceutical composition for thetreatment of so-called restless legs, the new use of certain compoundsknown to act as antihistamines, preferably in combination with quinine,for the preparation of a pharmaceutical composition for the treatment ofrestless legs, and a new method of treatment of restless legs.

There are several theories about the cause of the affliction experiencedas tingling and feelings of crawling in the-lower legs which occursparticularly at night and affects especially older patients. Thisaffliction is termed restless legs. Several methods of treatment havebeen tried for this affliction, some of which are described in ClinicalPharmacy, Volume 10, June 1991, pages 427-428. No treatment has,however, been particularly successful. This reference describes, amongother things, attempts to treat leg cramps by the use of quinine, butdoes not mention the use of quinine for the treatment of restless legs.

In accordance with the present invention, the surprising observation hasbeen made that certain substances known to be antihistamines can incertain cases give effective relief from the affliction of restlesslegs, and that a combination of such a substance with quinine givesextraordinary good relief.

Accordingly, the present invention relates to a pharmaceuticalcomposition for the treatment of restless legs, which is characterisedin that it comprises a combination of

A) quinine, preferably in the form of a pharmaceutically acceptable acidaddition salt thereof, and

B) a compound selected from the group consisting of

B1) compounds of the general formula (I)

 wherein R₁ is hydrogen or a straight or branched alkyl group, having1-4 carbon atoms,

 R₂ and R₃, which are equal or different, each represents hydrogen, ahalogen atom, a straight or branched alkyl or alkoxy group having 1-4carbon atoms, or a trifluoromethyl group, preferably in the form of apharmaceutically acceptable salt thereof, and

B2) compounds of the general formula (II)

 wherein X is hydrogen or a halogen atom, preferably chlorine, and R₄ isa methyl, ethyl or phenyl group

together with conventional pharmaceutically acceptable carriersubstances.

Compounds of the general formula (I) and their preparation are known,for example from U.S. Pat. No. 3,014,911. The compound most preferredfor use in the present invention is cyproheptadine˜4-(5H-dibenzo[a,d]cycloheptene-5-ylidene)-1-methyl-piperidine]. Thiscompound is a histamine H1 antagonist which is sold by Merck Sharp andDohme under the trade name Periactin® with indications acute and chronicallergy, pruritis, and vascular headache.

Compounds of the general formula (II) and processes for their productionare known, for example from U.S. Pat. No. 4,282,233. The compound mostpreferred for use in the present invention is loratadine[ethyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2b]pyridine-11-ylidene)-1-piperidine-carboxylate].This compound is sold by Schering-Plough AB, Stockholm, Sweden as ahistamine H1 antagonist under the trade name Clarityn, with indicationsallergic rhinitis and conjunctivitis, and histamine mediated pruritisand urticaria.

According to one embodiment of the pharmaceutical composition accordingto the invention, the two components A) and B) exist together in one andthe same pharmaceutical preparation together with conventionalpharmaceutically acceptable carriers in a suitable dosage unit form.

According to another embodiment, the pharmaceutical compositionaccording to the invention exists in the form of a kit containing thecomponents A) and B) each in a separate dosage unit. In this case thetwo components exist separately in tablet form with a known compositionfor the conventional use of the components in question.

According to a particularly preferred embodiment of the pharmaceuticalcomposition according to the invention said composition consists of akit with quinine hydrochloride in the form of a tablet containing 50-400mg, preferably 100-250 mg, quinine hydrochloride, and loratadine in theform of a tablet containing 5-15 mg, preferably 10 mg, loratadine.

According to another aspect of the present invention there is providedthe use of quinine for the preparation of a pharmaceutical compositionfor the treatment of restless legs in combination with a compound withthe general formula (I) or (II), as has been defined previously.According to the same aspect, the present invention also relates to theuse of a compound with the general formula (I) or (II) as has beendefined previously for the preparation of a pharmaceutical compositionfor the treatment of restless legs in combination with quinine.

According to a preferred embodiment of this use, the quinine exists inthe form of quinine hydrochloride, while loratadine is used as acompound with formula (II), the two substances being prepared separatelyas dosage units.

According to a further aspect of the invention there is provided the useof a compound of the general formula (II) as defined above for thepreparation of a pharmaceutical composition for the treatment ofrestless legs.

According to a still further aspect of the present invention there isprovided a method of treatment of restless legs, which method comprisesthe administration to a patient of a therapeutically effective amount ofa compound of formula (I) or (II) as has been defined previously incombination with quinine. According to a preferred embodiment of thismethod, the quinine is administered in the form of a tablet containing50-400 mg, preferably 100-250 mg, quinine hydrochloride, and loratadinein the form of a tablet containing 5-15 mg, preferably 10 mg,loratadine.

The present invention also provides a method of treatment of restlesslegs which method comprises administration to a patient of atherapeutically effective amount of a compound of the general formula(II) as defined above.

The invention will be further illustrated below by a number of examplesof the treatment of restless legs using a pharmaceutical composition inaccordance with the present invention and using a compound of thegeneral formula (II), with no connection to quinine, respectively.

The following preparations have been used in the experiments: Kinin NMPharma has been used as quinine. This is marketed by NM Pharma AB,Stockholm, Sweden in the form of tablets containing 100 mg or 250 mgquinine hydrochloride.

Loratadine, in the form of, Clarityn®, has been used as component B) inthe composition in accordance with the present invention. This is soldby Schering-Plough AB, Stockholm, Sweden in the form of tabletscontaining 10 mg loratadine.

EXAMPLE 1

A woman, date of birth 1943, had had prolonged affliction with tinglingwhich she had experienced as essentially disabling. She received 10 mgloratadine twice daily, which had a good effect. Since she occasionallyexperienced cramp-like sensations, quinine was employed at night, beinglater increased to 2×100 mg. She noticed, in addition to thedisappearance of the cramps, that the tingling was considerably reduced,and essentially disappeared completely with the combination ofloratadine and quinine.

EXAMPLE 2

A woman, date of birth 1960, with very severe paresthesia in the legs atnight, occasionally also during the day, became totally free of theaffliction with loratadine 10 mg and quinine 100 mg daily.

EXAMPLE 3

A woman, date of birth 1936, with severe tingling in the legs mainly atnight, with occasional calf cramps, became essentially free ofaffliction with a combination of loratadine and quinine.

EXAMPLE 4

A woman, date of birth 1924, with over 10 years' affliction withtingling in the legs and, less often, calf cramps, became essentiallysymptom free with a combination of loratadine 10 mg and quinine 100 mg.The paresthesia returned within ½ to 1 day of discontinuing thetreatment and were then just as severe as before the treatment.

EXAMPLE 5

A man, date of birth 1909, with restless legs and occasional calf crampsreceived 10 mg loratadine and 100 mg quinine, on which both symptomsdisappeared. The treatment continued for several months with excellentresults, but was discontinued by the patient due to other problems.

EXAMPLE 6

A woman, date of birth 1924, received loratadine 10 mg and quinine 100mg, and experienced a remarkable improvement, becoming essentially freeof affliction from restless legs when the treatment started about 5months ago.

EXAMPLE 7

A woman, date of birth 1946, who had had both severe tingling andrelatively frequent cramps in the legs. Both symptoms disappeared after1 month's treatment with loratadine 10 mg and quinine 100 mg.

EXAMPLE 8

A woman, date of birth 1910, with paresthesia and aching calves, wastreated with loratadine 10 mg and quinine 100 mg. After 3 months'treatment, the patient experienced a certain improvement and isessentially free of affliction with paresthesia while the treatment hashad poor effect on the aching calves. No circulation disturbance hasbeen found to explain this.

EXAMPLE 9

A woman, date of birth 1921, with long-standing severe tingling becametotally free of affliction with a combination of loratadine 10 mg andquinine 100 mg. The problems returned on attempts to cease treatment.

EXAMPLE 10

A woman, date of birth 1940, with severe tingling for 10 years andoccasional cramps in the calves. A combination treatment with 10 mgloratadine and 1-2 100 mg tablets quinine at night gave completeregression of the afflictions after about 1 week. The problems returnedif the treatment was ceased.

EXAMPLE 11

A woman, date of birth 1926, with severe tingling in both legs andoccasional aches for over 10 years was treated with loratadine 10 mg andquinine 100 mg. The patient has previously been operated for Baker'scysts in the hollow of the knee which were thought to be the cause ofher problems. The problems persisted, however. After treatment inaccordance with the present invention, the patient experienced aremarkable change, becoming completely free of symptoms in the lowerlegs with which she had been afflicted for years.

EXAMPLE 12

A woman, date of birth 1914, with tingling since 1986 which had beeninvestigated with magnet tomography and operated to remove spinalstenosis, etc. None of these measures, however, had the slightest effecton her night-time paresthesia. The patient underwent a trial series inwhich she received 1 tablet quinine 100 mg at night-time for the firstweek, without effect. Two tablets of 100 mg quinine were applied duringthe second week, while during the third week 10 mg loratadine on its ownwas applied, without effect. During the forth week, 2 100 mg tabletsquinine were combined with 1 10 mg tablet loratadine. After two days,the paresthesia disappeared, as did the leg aches which she had had formore than 10 years. However, after a few months the tingling started toreturn around 3 a.m., upon which the earlier dose which had been takenaround 11 p.m. was supplemented with a second dose 4-5 hours later. Theproblems disappeared again, about 30 minutes after the dose.

The following two examples (Examples 13 and 14) show that results onrestless legs in certain patients can be achieved by loratadine on itsown, and not in combination with quinine.

EXAMPLE 13

A woman, date of birth 1914, who had had long-standing severe bi-lateralaffliction with restless legs, received in March 1995 a dosage of 10 mgloratadine in the morning. Within 2 weeks a clear improvement was seenand the patient, who has since been under observation for over a year,is now considered to be essentially free of affliction.

EXAMPLE 14

A woman, date of birth 1947, with tingling on prolonged sitting andhypertonia received 10 mg loratadine daily with very good effect.

What is claimed is:
 1. A pharmaceutical composition for the treatment ofrestless legs, characterized in that it consists of a combination of A)quinine, and B) a compound selected from the group consisting of B1)compounds of the general formula (I)

 wherein R₁ is hydrogen or a straight or branched alkyl group, having1-4 carbon atoms,  R₂ and R₃, which may be equal or different, eachrepresents hydrogen, a halogen atom, a straight or branched alkyl oralkoxy group having 1-4 carbon atoms, or a trifluoromethyl group, andB2) compounds of the general formula (II)

 wherein X is hydrogen or a halogen atom, and R₄ is a methyl, ethyl orphenyl group together with conventional pharmaceutically acceptablecarrier substances.
 2. The pharmaceutical composition according to claim1, characterized in that the compound of the general formula (I) iscyproheptadine.
 3. The pharmaceutical composition according to claim 1,characterized in that the compound of the general formula (II) isloratadine.
 4. The pharmaceutical composition according to claim 1,characterized in that it is a kit of components A) and B), each asseparate dosage units.
 5. The pharmaceutical composition according toclaim 4, characterized in that it is a kit with quinine hydrochloride intablet form, with tablets containing 50-4000 mg quinine hydrochlorideand loratadine in tablet form, each tablet containing 5-15 mgloratadine.
 6. The pharmaceutical composition according to claim 1,wherein said halogen atom for said X is chlorine.
 7. The pharmaceuticalcomposition according to claim 1, wherein said quinine and said B1 andB2 compounds are in the form of a pharmaceutically acceptable saltthereof.
 8. The pharmaceutical composition according to claim 2, whereinsaid cyproheptadine is in the form of its chloride.
 9. Thepharmaceutical composition according to claim 5, wherein said quininehydrochloride containing tablet form contains 100-250 mg of quininehydrochloride.
 10. The pharmaceutical composition according to claim 5,wherein said loratadine containing tablet form contains 10 mg ofloratadine.
 11. A method of treatment of restless legs which methodcomprises the administration to a patient of a therapeutically effectivedose of a compound of the formula (I) or (II) as defined in claim 1 incombination with quinine.
 12. The method according to claim 11, whereinquinine is administered in tablet form, each tablet containing 50-400 mgquinine hydrochloride and loratadine in tablet form, each tabletcontaining 5-15 mg loratadine.
 13. The method according to claim 12,wherein said quinine hydrochloride containing tablet form contains100-250 mg of quinine hydrochloride.
 14. The method according to claim12, wherein said loratadine containing tablet form contains 10 mg ofloratadine.
 15. The method according to claim 11, wherein an effectivedose of the compound of formula (II) in combination with quinine isadministered.
 16. The method according to claim 12, wherein said quininehydrochloride and loratadine are prepared in separate dosage units.